2-phenyl-3-heteroarylpropionic acid derivative or salt thereof and medicine containing the same

ABSTRACT

The present invention relates to a 2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof, and also relates to a pharmaceutical agent and a VLA-4 and/or LPAM-1 antagonist each of which contains the same as an active ingredient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 National Phase Entry Application of co-pendingInternational Application PCT/JP02/08921, filed 3 Sep. 2002, whichdesignated the U.S. and which claims the benefit under 35 U.S.C. § 119of Japanese Patent Application No. 2001-276371, filed 12 Sep. 2001.

TECHNICAL FIELD

The present invention relates to a novel 2-phenyl-3-heteroarylpropionicacid derivative or a salt thereof and a pharmaceutical agent containingthe same as an active ingredient and a cell adhesion inhibitor.

TECHNICAL BACKGROUND

An adhesion phenomenon is essential to a complicated life phenomenonresulted from intercellular interaction such as activation, migration,proliferation, differentiation, etc., of cells. And, cell adhesionmolecules classified as integrin, immunoglobulin, selectin, cadherin,etc., are involved in the above cell-cell or cell-extracellular matrixinteractions. The integrin family has an αβ-heterodimer structure and 16different integrin α chains and 8 different integrin β chains have beenidentified. Integrin VLA-4 (α4β1) as one of them expresses withinlymphocyte, eosinophils, basophils and monocyte, and VCAM-1 andfibronectin are ligands thereof. That is, VLA-4 plays an important rolein cell-cell interactions and cell-extracellular matrix interactionsmediated by VCAM-1 and fibronectin. Further, integrin LPAM-1 (α4β7)expresses within lymphocyte, eosinophils, basophils and monocyte, andVCAM-1, fibronectin and MadCAM-1 are ligands thereof. Meanwhile, forleucocytes' functioning in the inflammatory tissue, leucocytescirculating with blood are required to pass through the vascularendothelial cells and infiltrate the inflammatory site. Binding ofeither VLA-4 or LPAM-1 with either VCAM-1 or MadCAM-1 is one of the mostimportant mechanisms that produce an intense adhesion between leukocytesand vascular endothelial cells. Inflammatory cells such as T lymphocyte,B lymphocyte, monocyte and eosinophils express VLA-4 and LPAM-1, andVLA-4 and LPAM-1 strongly take part in the infiltration of these cellsto an inflammatory lesion. The adhesion molecules play an essential rolein the activation of cells through cell-cell interactions, and it hasbeen made clear that the VLA-4/VCAM-1 mechanism activates eosinophils tocause degranulation, and that a signal through VLA-4 takes part in theactivation of antigen-specific proliferation of lymphocytes as well.

For elucidating the roles of VLA-4 and LPAM-1 in an inflammation,several studies have been made to inhibit this intermolecular bindingusing monoclonal antibody. For example, an anti-α4 monoclonal antibodyinhibits the adhesion of VLA-4 expressing Ramos cells onto humanumbilical venous endothelial cells (HUVEC) or VCAM-1-gene-transferredCOS cells. The antibody has shown therapeutic and/or prophylacticeffects in several animal models. For example, significant effects havebeen demonstrated on a rat adjuvant induced arthritis model (Barbadilloet al., Arthritis Rheumatol., 1993, 36, 95), and contacthypersensitivity and delayed-type hypersensitivity model (Ferguson andKupper, J. Immunol., 1993, 150, 1172; Chisholm et al., Eur. J. Immunol.,1993, 23, 682). Further, the action of the antibody has been evaluatedon experimental autoimmune encephalomyelitis (Yednock, Nature, 1992,356, 63), asthma model (Abraham et al., J. Clin. Invest., 1993, 93, 776)and inflammatory bowel disease (IBD) model (Podolsky et al., J. Clin.Invest., 1993, 92, 372). Further, it has been shown that the celladhesion with VLA-4 plays some roles in rheumatoid arthritis, nephritis,diabetes, systemic lupus erythematosus, delayed-type allergy, multiplesclerosis, arteriosclerosis, organ transparent and various malignanttumors.

Therefore, blocking of VLA-4 (α4β1) and/or LPAM-1 (α4β7) integrins withan appropriate antagonist is effective for the therapeutical treatmentof the above various diseases including inflammation diseases.

Several low-molecular-weight compounds have been already proposed asVLA-4 and/or LPAM-1 antagonists. They are described in InternationalPatent Publications Nos. WO96/22966, WO98/53817, WO01/14328, WO99/06431,WO99/06432, WO99/06436, WO99/10312, WO99/48879, WO00/18759, WO00/20396,WO99/36393, WO99/52898, WO99/62901, WO00/67746 and WO02/08206. Thosecompounds described in these Publications have a urea structure orphenylalanine structure and do not have any2-phenyl-3-heteroarylpropionic acid structure of the present invention.All conventional compounds also have problems that they lackbioavailability in oral administration and are easily decomposed invivo. There is therefore required a compound that has propertiesdesirable for therapeutical treatment and prophylaxis and which exhibitsan antagonistic function against VLA-4 and/or LPAM-1.

DISCLOSURE OF THE INVENTION

The present invention has been made for therapeutical treatment andprophylaxis of the above diseases mediated by VLA-4 and LPAM-1. It is anobject of the present invention to provide a novel2-phenyl-3-heteroarylpropionic acid derivative as a compound that isexcellent in oral absorption and an pharmacokinetics and which exhibitsa VLA-4 and/or LPAM-1 antagonistic function or a salt thereof.

It is also another object of the present invention to provide a VLA-4and/or LPAM-1 antagonist useful for the therapeutical treatment andprophylaxis of diseases mediated by VLA-4 and/or LPAM-1 and apharmaceutical agent.

For achieving the above object, the present inventors have made diligentstudies and as a result have found that a 2-phenyl-3-heteroarylpropionicacid derivative has excellent inhibitory effect against α4 integrin, andthe present invention has been accordingly completed.

That is, the present invention provides

(1) a 2-phenyl-3-heteroarylpropionic acid derivative of the generalformula (I),

wherein Het is an aromatic heterocyclic ring and each of X¹ to X⁵ isindependently a hydrogen atom, a substituent having no organic group, ahydrocarbon or heteroaryl group that bonds to the benzene ring or thearomatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group, —NR¹R², —N(R¹)COR², —N(R¹)SO₂R²,—N(R¹)CONR²R³, —OCONR¹R² or —CONR¹R², (in which each of R¹, R² and R³ isindependently a hydrogen atom or a hydrocarbon or heteroaryl group whichmay have an oxygen atom at a terminal bonding site, and R¹ and R² maybond, or R² and R³ may bond, to each other and form a ring that maycontain a hetero atom, a double bond or a substituent,) provided thatwhen two substituents of X¹, X² and X³ bond to adjacent carbon atoms,the two substituents may bond to each other and form a benzene ring or amethylenedioxy group, or a salt thereof,

(2) a 2-phenyl-3-heteroarylpropionic acid derivative or a salt thereofas recited in the above (1), wherein at least one of X⁴ and X⁵ in thegeneral formula (I) is a group represented by any one of the generalformulae (II) to (V),

—OCH₂—R¹¹  (III)—CH═CH—R¹¹  (IV)—C≡C—R¹¹  (V)

wherein R⁴ is a hydrogen atom or an alkyl group having 1 to 15 carbonatoms and R¹¹ is a group represented by the general formula (VI) or(VII),

wherein each of R⁵ and R⁶ is independently a hydrogen atom, asubstituent having no organic group or a hydrocarbon or heteroaryl groupthat bonds to the benzene ring or the aromatic heterocyclic ringdirectly or through an oxygen atom, a sulfur atom, an oxycarbonyl group,a carbonyl group, a carbonyloxy group, a sulfonyl group or a sulfinylgroup, —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷)SO₂R⁸, —N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸, inwhich each of R⁷, R⁸ and R⁹ is independently a hydrogen atom or ahydrocarbon or heteroaryl group which may have an oxygen atom at aterminal bonding site, and R⁷ and R⁸ may bond, or R⁸ and R⁹ may bond, toeach other and form a ring that may contain a hetero atom, a double bondor a substituent, Het is an aromatic heterocyclic ring and R¹⁰ is ahydrogen atom or an alkyl group having 1 to 15 carbon atoms,

(3) a 2-phenyl-3-heteroarylpropionic acid derivative or a salt thereofas recited in the above (1) or (2), wherein at least one of X¹, X² andX³ in the general formula (I) is —NR¹R², —N(R¹)COR², —N(R¹)SO₂R²,—N(R¹)CONR²R³, an alkyl group, an alkoxy group, an aryl group, aheteroaryl group, an alkoxycarbonyl group, a halogen atom, a cyano groupor an alkylthio group,

(4) a 2-phenyl-3-heteroarylpropionic acid derivative or a salt thereofas recited in the above (3), wherein at least one of X¹, X² and X³ is—N(R¹) COR² substituted on the 3-position,

(5) a pharmaceutical agent containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4),

(6) a therapeutic or prophylactic pharmaceutical agent for aninflammatory patient having a disease state in which a cell adhesionprocess takes part, which pharmaceutical agent contains, as an activeingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in any one of the above (1) to (4),

(7) a therapeutic or prophylactic pharmaceutical agent for aninflammatory patient having a disease state in which a cell adhesionprocess caused by α4 integrin takes part, which pharmaceutical agentcontains, as an active ingredient, a 2-phenyl-3-heteroarylpropionic acidderivative or a salt thereof as recited in any one of the above (1) to(4),

(8) A therapeutic or prophylactic method for an inflammatory patienthaving a disease state in which a cell adhesion process takes part,which comprises administering a pharmaceutical agent containing, as anactive ingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or asalt thereof as recited in any one of the above (1) to (4),

(9) A therapeutic or prophylactic method for an inflammatory patienthaving a disease state in which a cell adhesion process caused by α4integrin takes part, which comprises administering a pharmaceuticalagent containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4),

(10) a cell adhesion inhibitor containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4),

(11) an α4 integrin inhibitor containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4),

(12) a VLA-4 antagonist containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4), and

(13) a LPAM-1 antagonist containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4).

PREFERRED EMBODIMENT OF THE INVENTION

In the present specification, it should be understood that the specifiednumber of carbon atoms refers to the number of carbon atoms existing inthe main portion of each group and does not include the number of carbonatoms existing in a substituent portion attached to said main portion.For example, in an alkyl group having an aryl group as a substituent(i.e., an arylalkyl group), any specified number of carbon atoms refersto the number of carbon atoms existing only in the alkyl portionconstituting the arylalkyl group and does not include the number ofcarbon atoms of an aryl portion.

The 2-phenyl-3-heteroarylpropionic acid derivative or the salt thereofin the present invention is a compound having a structure of the generalformula (I) or a salt thereof.

In the above general formula (I), Het is an aromatic heterocyclic ring,and each of X¹ to X⁵ is independently a hydrogen atom, a substituenthaving no organic group, a hydrocarbon or heteroaryl group that bonds tothe benzene ring or the aromatic heterocyclic ring directly or throughan oxygen atom, a sulfur atom, an oxycarbonyl group, a carbonyl group, acarbonyloxy group, a sulfonyl group or a sulfinyl group, —NR¹R²,—N(R¹)COR², —N(R¹)SO₂R², —N(R¹)CONR²R³, —OCONR¹R² or —CONR¹R².

The above aromatic heterocyclic ring represented by Het includes anaromatic heterocyclic ring containing 1 to 3 hetero atoms selected fromnitrogen, oxygen and sulfur atoms. The above aromatic heterocyclic ringincludes both a non-substituted aromatic heterocyclic ring and anaromatic heterocyclic ring having a substituent, and it further includesan aromatic heterocyclic ring having a structure formed of 2 or morerings that are fused (The term “aromatic heterocyclic ring” in thepresent specification is used in the above sense unless otherwisespecified). Specific examples thereof include heterocyclic rings such asfuran, thiophene, pyrrole, oxazole, thiazole, imidazole, triazole,tetrazole, pyridine, pyrimidine, indole, benzofuran, thianaphthene andpurine.

Examples of the above substituent having no organic group include ahalogen atom, a nitro group, a cyano group, a hydroxyl group and acarboxyl group. Specific examples of the halogen atom include a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the above hydrocarbon or heteroaryl group that bonds to abenzene ring or the aromatic heterocyclic ring directly or through anoxygen atom, a sulfur atom, an oxycarbonyl group, a carbonyl group, acarbonyloxy group, a sulfonyl group or a sulfinyl group include an alkylgroup having 1 to 15 carbon atoms, an alkenyl group having 2 to 15carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an arylgroup having 6 to 10 carbon atoms, a heteroaryl group, an alkoxy grouphaving 1 to 15 carbon atoms, an aryloxy group having 6 to 10 carbonatoms, a heteroaryloxy group, an alkoxycarbonyl group having 2 to 16carbon atoms, an aryloxycarbonyl group having 7 to 11 carbon atoms, aheteroaryloxycarbonyl group, an alkylcarbonyl group having 2 to 16carbon atoms, an arylcarbonyl group having 7 to 11 carbon atoms, aheteroarylcarbonyl group, an alkylcarbonyloxy group having 2 to 16carbon atoms, an arylcarbonyloxy group having 7 to 11 carbon atoms, aheteroarylcarbonyloxy group, an alkylthio group having 1 to 15 carbonatoms, an arylthio group having 6 to 10 carbon atoms, a heteroarylthiogroup, an alkylsulfonyl group having 1 to 15 carbon atoms, anarylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonylgroup, an alkylsulfinyl group having 1 to 15 carbon atoms, anarylsulfinyl group having 6 to 10 carbon atoms, a heteroarylsulfinylgroup.

The above alkyl group having 1 to 15 carbon atoms includes both anon-substituted alkyl group and an alkyl group having a substituent, thealkyl chain thereof may be linear or branched, and further, the abovealkyl group may be a cycloalkyl group having a structure of 1 or morecyclic rings and having 3 to 15 carbon atoms (in the presentspecification, the term “alkyl group” is used in the above sense unlessotherwise specified). Specific examples of the non-substituted alkylgroup having 1 to 15 carbon atoms include linear or branched alkylgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, tert-amyl, 3-methylbutyl, neopentyl,n-hexyl and n-decyl. Specific examples of the cycloalkyl group having 3to 15 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

When the above alkyl group has a substituent, the substituent includes ahalogen atom, a nitro group, a cyano group, a hydroxy group, a carboxylgroup, an aryl group having 6 to 10 carbon atoms, a heteroaryl group,—OR, —SR, —SOR, SO₂R— and —NRR′ (in the present specification, asubstituent on the alkyl group portion of a substituent containing analkyl group (e.g., an alkoxy group, an alkylthio group, etc.) similarlyincludes the above substituents unless otherwise specified). Each of theabove R and R′ is independently a hydrogen atom, an alkyl group having 1to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, anaryl group having 6 to 10 carbon atoms or a heteroaryl group. When theabove alkyl group is an alkyl group substituted with a halogen atom,i.e., a halogenated alkyl group, the halogenated alkyl group refers to ahalogenated alkyl group having 1 to 15 carbon atoms, and specificexamples thereof are trichloromethyl, trifluoromethyl, 1-chloroethyl and2,2,2-trifluoroethyl. When the above alkyl group is an alkyl groupsubstituted with an aryl group, the aryl group includes a monocyclic orbicyclic aryl group having 6 to 10 carbon atoms and containing nosubstituent or containing 1 to 3 substituents. Specific examples thereofinclude benzyl, 2-phenethyl, 1-phenethyl, 1-phenylpropyl,1-naphthylmethyl and 2-naphthylmethyl. The aryl portion of the abovearylalkyl group may have a substituent, and the substituent includes analkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 7carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxylgroup, a carboxyl group, an aryl group having 6 to 10 carbon atoms andan aryloxy group having 6 to 10 carbon atoms.

When the above alkyl group is an alkyl group substituted with aheteroaryl group, i.e., a heteroarylalkyl group, specific examplesthereof include 2-pyridylmethyl, 3-furylmethyl and 2-(2-thienyl)ethyl.When the above alkyl group is an alkyl group substituted with an alkoxygroup, i.e., an alkoxyalkyl group, the alkoxy group refers to an alkoxygroup having 1 to 10 carbon atoms, and specific examples thereof includemethoxymethyl, ethoxymethyl, isopropoxymethyl, 2-methoxyethyl and1-methoxyisopropyl.

Further, the above alkyl group having a substituent includes alkylgroups represented by —(CH₂)—NRR′, —(CH₂)_(n)—OR, —(CH₂)_(n)—SR,—(CH₂)_(n)—SOR and —(CH₂)_(n)—SO₂R. In this case, n is an integer of 1to 3, R and R′ are as defined above, and specific examples thereof arealso as described above.

The above alkenyl group having 2 to 15 carbon atoms includes both anon-substituted alkenyl group and an alkenyl group having a substituent,the alkenyl chain thereof may be linear or branched, and further, theabove alkenyl group may be a cycloalkenyl group having a structure of 1or more cyclic rings (the term “alkenyl group” in the presentspecification will be used in this sense unless otherwise specified).When the above alkenyl group has a substituent, the substituent includesa halogen atom, a nitro group, a cyano group, a hydroxyl group, acarboxyl group, an aryl group having 6 to 10 carbon atoms, a heteroarylgroup, —OR—, —SR, —SOR, —SO₂R and —NRR′. The above R and R′ are asdefined above. Specific examples of the above alkenyl group includevinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl and1,2-dimethylpropenyl. Further, when the above alkenyl group is analkenyl group substituted with an aryl group, i.e., an arylalkenylgroup, the aryl group constituting the above arylalkenyl group is asdefined with regard to the above aryl group, and specific examplesthereof include 2-phenylvinyl, and the like. Further, the aryl portionof the above arylalkenyl group may have a substituent, and thesubstituent includes an alkyl group having 1 to 6 carbon atoms, analkoxy group having 1 to 7 carbon atoms, a halogen atom, a nitro group,a cyano group, a hydroxy group, a carboxyl group, an aryl group having 6to 10 carbon atoms and an aryloxy group having 6 to 10 carbon atoms.

The above alkynyl group having 2 to 15 carbon atoms includes both anon-substituted alkynyl group and an alkynyl group having a substituent,and the alkynyl chain thereof may be linear or branched (the term“alkynyl group” in the present specification will be used in this senseunless otherwise specified). When the above alkynyl group has asubstituent, the substituent includes a halogen atom, a nitro group, acyano group, a hydroxyl group, a carboxyl group, an aryl group having 6to 10 carbon atoms, a heteroaryl group, —OR—, —SR, —SOR, —SO₂R and—NRR′. The above R and R′ are as defined above. Specific examples of theabove alkynyl group include hexynyl, phenylethynyl and pyridylethynyl.Further, when the above alkynyl is an alkynyl substituted with an arylgroup, i.e., an arylalkynyl group, the aryl group constituting the abovearylalkynyl group is as defined with regard to the above aryl group. Thearyl portion of the above arylalkynyl group may further have asubstituent, and the substituent includes an alkyl group having 1 to 6carbon atoms, an alkoxy group having 1 to 7 carbon atoms, a halogenatom, a nitro group, a cyano group, a carboxyl group, a hydroxyl group,an aryl group having 6 to 10 carbon atoms and an aryloxy group having 6to 10 carbon atoms.

The above aryl group having 6 to 10 carbon atoms includes both anon-substituted aryl group and an aryl group having a substituent (theterm “aryl group” in the present specification will be used in thissense unless otherwise specified). Specific examples of thenon-substituted aryl group having 6 to 10 carbon atoms include phenyl,1-naphthyl and 2-naphthyl.

When the above aryl group has a substituent, the substituent includes analkyl group having 1 to 10 carbon atoms, a halogen atom, a nitro group,a cyano group, a hydroxyl group, a carboxyl group, an aryl group having6 to 10 carbon atoms, a heteroaryl group, —OR, —NRR′—, —SR, —SOR and—SO₂R (in the present specification, a substituent on the aryl groupportion of a substituent containing an aryl group (e.g., an aryloxygroup, an arylthio group, etc.) similarly includes the abovesubstituents unless otherwise specified). R and R′ are as defined above,and specific examples thereof are also as specified above. The arylgroup having a substituent includes o-tolyl, 2,6-dimethoxyphenyl,3-chlorophenyl, 2-cyanophenyl and biphenyl.

The above heteroaryl group refers to an aromatic heterocyclic ring groupcontaining at least one hetero atom selected from 1 to 3 kinds of atomssuch as nitrogen atoms, oxygen atoms and sulfur atoms, and the aboveheteroaryl group includes a non-substituted heteroaryl group and aheteroaryl group having a substituent (the term “heteroaryl group” inthe present specification will be used in this sense unless otherwisespecified). When the above heteroaryl group has a substituent, thesubstituent includes a halogen atom, a nitro group, a cyano group, ahydroxyl group, a carboxyl group, the above alkyl group, the above arylgroup, —OR—, —NRR′, —SR, —SOR and —SO₂R (in the present specification, asubstituent on the aryl group portion of a substituent containing aheteroaryl group (e.g., a heteroaryloxy group, a heteroarylthio group,etc.) similarly includes the above substituents unless otherwisespecified). R and R′ are as defined above, and specific examples thereofare also as specified above. Specific examples of the above heteroarylgroup include furyl, thienyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, pyridyl, pyrazyl, indolyl, tetrazolyl and quinolyl.

The above alkoxy group having 1 to 15 carbon atoms includes both anon-substituted alkoxy group and an alkoxy group having a substituent,and the alkyl group constituting the alkoxy group is as defined withregard to the above alkyl group (the term “alkoxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the alkyl group portion thereof and specific examplesthereof are also as described with regard to the above alkyl group.Specific examples of the non-substituted alkoxy group having 1 to 15carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, tert-amyloxy,neopentyloxy and n-hexyloxy.

When the above alkoxy group is an alkoxy group substituted with analkoxy group, i.e., an alkoxyalkoxy group, specific examples thereofinclude methoxymethoxy and methoxyethoxymethoxy. When the above alkoxygroup is an alkoxy group substituted with an aryl group, i.e., anarylalkoxy group, the aryl group as a substituent refers to an arylgroup having 6 to 10 carbon atoms. Specific examples of the abovearylalkoxy group include benzyloxy, 1-naphthylmethoxy,2-naphthylmethoxy, 1-phenylethoxy, 4-methoxybenzyloxy, 2-phenylethoxyand 3-phenylpropoxy. When the above alkoxy group is an alkoxy groupsubstituted with a heteroaryl group, i.e., a heteroarylalkoxy group,specific examples thereof include 2-pyridylmethoxy,(3,5-dichloropyrid-4-yl)methoxy and 2-(indol-1-yl)ethoxy.

The above aryloxy group having 6 to 10 carbon atoms includes both anon-substituted aryloxy group and an aryloxy group having a substituent,and the aryl group constituting the aryloxy group is as defined withregard to the above aryl group (the term “aryloxy group” in the presentinvention will be used in this sense unless otherwise specified). Thesubstituent on the aryl group portion and specific examples thereof arealso as described with regard to the above aryl group. Specific examplesof the non-substituted aryloxy group having 6 to 10 carbon atoms includephenoxy and naphthoxy. Specific examples of the above aryloxy grouphaving a substituent include 2-chlorophenoxy.

The above heteroaryloxy group includes both a non-substitutedheteroaryloxy group and a heteroaryloxy group having a substituent, andthe heteroaryl group constituting the heteroaryloxy group is as definedwith regard to the above heteroaryl group (the term “heteroaryloxygroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the heteroaryl group portionand specific examples thereof are also as described with regard to theabove heteroaryl group. Specific examples of the above heteroaryloxygroup include 4-pyridyloxy and 2-pyrimidyloxy.

The above alkoxycarbonyl group having 2 to 16 carbon atoms includes botha non-substituted alkoxycarbonyl group and an alkoxycarbonyl grouphaving a substituent, and the alkyl group constituting thealkoxycarbonyl group is as defined with regard to the above alkyl group(the term “alkoxycarbonyl group” in the present specification will beused in this sense unless otherwise specified). The substituent on thealkyl group portion and specific examples thereof are also as describedwith regard to the above alkyl group. Specific examples of the abovealkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl.

The above aryloxycarbonyl group having 7 to 11 carbon atoms includesboth a non-substituted aryloxycarbonyl group and an aryloxycarbonylgroup having a substituent, and the aryl group constituting thearyloxycarbonyl group is as defined with regard to the above aryl group(the term “aryloxycarbonyl group” in the present specification will beused in this sense unless otherwise specified). The substituent on thearyl group portion and specific examples thereof are also as describedwith regard to the above aryl group. Specific examples of the abovearyloxycarbonyl group include phenoxycarbonyl and naphthoxycarbonyl.

The above heteroaryloxycarbonyl group includes both a non-substitutedheteroaryloxycarbonyl group and a heteroaryloxycarbonyl group having asubstituent, and the heteroaryl group constituting theheteroaryloxycarbonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroaryloxycarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl groupabove. Specific examples of the above heteroaryloxycarbonyl groupinclude 4-pyridyloxycarbonyl.

The above alkylcarbonyl group having 2 to 16 carbon atoms include both anon-substituted alkylcarbonyl group and an alkylcarbonyl group having asubstituent, and the alkyl group constituting the alkylcarbonyl group isas defined with regard to the above alkyl group (the term “alkylcarbonylgroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the alkyl group portion andspecific examples thereof are as described with regard to the abovealkyl group. Specific examples of the above alkylcarbonyl group includeacetyl, propionyl, n-butanoyl and isobutanoyl.

The above arylcarbonyl group having 7 to 11 carbon atoms includes both anon-substituted arylcarbonyl group and an arylcarbonyl group having asubstituent, and the aryl group constituting the arylcarbonyl group isas defined with regard to the above aryl group (the term “arylcarbonylgroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the aryl group portion andspecific examples thereof are also as described with regard to the abovearyl group. Specific examples of the above arylcarbonyl group include3-chlorobenzoyl.

The above heteroarylcarbonyl group includes both a non-substitutedheteroarylcarbonyl group and a heteroarylcarbonyl group having asubstituent, and the heteroaryl group constituting theheteroarylcarbonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylcarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylcarbonyl group include2-thiophenecarbonyl.

The above alkylcarbonyloxy group having 2 to 16 carbon atoms includesboth a non-substituted alkylcarbonyloxy group and an alkylcarbonyloxygroup having a substituent, and the alkyl group constituting thealkylcarbonyloxy group is as defined with regard to the above alkylgroup (the term “alkylcarbonyloxy group” in the present specificationwill be used in this sense unless otherwise specified). The substituenton the alkyl group portion and specific examples thereof are also asdescribed with regard to the above alkyl group. Specific examples of theabove alkylcarbonyloxy group include acetoxy.

The above arylcarbonyloxy group having 7 to 11 carbon atoms includesboth a non-substituted arylcarbonyloxy group and an arylcarbonyloxygroup having a substituent, and the aryl group constituting thearylcarbonyloxy group is as defined with regard to the above aryl group(the term “arylcarbonyloxy group” in the present specification will beused in this sense unless otherwise specified). The substituent on thearyl group portion and specific examples thereof are also as describedwith regard to the above aryl group. Specific examples of the abovearylcarbonyloxy group include benzoyloxy.

The above heteroarylcarbonyloxy group includes both a non-substitutedheteroarylcarbonyloxy group and a heteroarylcarbonyloxy group having asubstituent, and the heteroaryl group constituting theheteroarylcarbonyloxy group is as defined with regard to the aboveheteroaryl group (the term “heteroarylcarbonyloxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylcarbonyloxy group include3-pyridinecaronyloxy.

The above alkylthio group having 1 to 15 carbon atoms includes both anon-substituted alkylthio group and an alkylthio group having asubstituent, and the alkyl group constituting the alkylthio group is asdefined with regard to the above alkyl group (the term “alkylthio group”in the present specification will be used in this sense unless otherwisespecified). The substituent on the alkyl group portion and specificexamples thereof are also as described with regard to the above alkylgroup. Specific examples of the above alkylthio group includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,sec-butylthio and tert-butylthio.

The above arylthio group having 6 to 10 carbon atoms includes both anon-substituted arylthio group and an arylthio group having asubstituent, and the aryl group constituting the arylthio group is asdefined with regard to the above aryl group (the term “arylthio group”in the present specification will be used in this sense unless otherwisespecified). The substituent on the aryl group portion and specificexamples thereof are also as described with regard to the above arylgroup. Specific examples of the above arylthio group include phenylthioand tolylthio.

The above heteroarylthio group includes both a non-substitutedheteroarylthio group and a heteroarylthio group having a substituent,and the heteroaryl group constituting the heteroarylthio group is asdefined with regard to the above heteroaryl group (the term“heteroarylthio group” in the present specification will be used in thissense unless otherwise specified). The substituent on the heteroarylgroup portion and specific examples thereof are also as described withregard to the above heteroaryl group. Specific examples of the aboveheteroarylthio group include pyridylthio, imidazolidylthio andthienylthio.

The above alkylsulfonyl group having 1 to 15 carbon atoms includes botha non-substituted alkylsulfonyl group and an alkylsulfonyl group havinga substituent, and the alkyl group constituting the alkylsulfonyl groupis as defined with regard to the above alkyl group (the term“alkylsulfonyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the alkyl groupportion and specific examples thereof are also as described with regardto the above alkyl group. Specific examples of the above alkylsulfonylgroup include methanesulfonyl, ethanesulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

The above arylsulfonyl group having 6 to 10 carbon atoms includes both anon-substituted arylsulfonyl group and an arylsulfonyl group having asubstituent, and the aryl group constituting the arylsulfonyl group isas defined with regard to the above aryl group (the term “arylsulfonylgroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the aryl group portion andspecific examples thereof are also as described with regard to the abovearyl group. Specific examples of the above arylsulfonyl group includebenzenesulfonyl, fluorobenzenesulfonyl and tosyl.

The above heteroarylsulfonyl group includes both a non-substitutedheteroarylsulfonyl group and an heteroarylsulfonyl group having asubstituent, and the heteroaryl group constituting theheteroarylsulfonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylsulfonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylsulfonyl group include2-pyridylsulfonyl and 2-thienylsulfonyl.

The above alkylsulfinyl group having 1 to 15 carbon atoms includes botha non-substituted alkylsulfinyl group and an alkylsulfinyl group havinga substituent, and the alkyl group constituting the alkylsulfinyl groupis as defined with regard to the above alkyl group (the term“alkylsulfinyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the alkyl groupportion and specific examples thereof are also as described with regardto the above alkyl group. Specific examples of the above alkylsulfinylgroup include methanesulfinyl, ethanesulfinyl, n-propylsulfinyl,isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl andtert-butylsulfinyl.

The above arylsulfinyl group having 6 to 10 carbon atoms includes both anon-substituted arylsulfinyl group and an arylsulfinyl group having asubstituent, and the aryl group constituting the arylsulfinyl group isas defined with regard to the above aryl group (the term “arylsulfinylgroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the aryl group portion andspecific examples thereof are also as described with regard to the abovearyl group. Specific examples of the above arylsulfinyl group includebenzenesulfinyl.

The above heteroarylsulfinyl group includes both a non-substitutedheteroarylsulfinyl group and a heteroarylsulfinyl group having asubstituent, and the heteroaryl group constituting theheteroarylsulfinyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylsulfinyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylsulfinyl group include2-pyridylsulfinyl and 2-thienylsulfinyl.

In the above —NR¹R², —N(R¹)COR², —N(R¹)SO₂R², —N(R¹)CONR²R³, —OCONR¹R²and —CONR¹R², each of R¹, R² and R³ is independently a hydrogen atom ora hydrocarbon or heteroaryl group that may have an oxygen atom at aterminal bonding site. Examples of the hydrocarbon or heteroaryl groupthat may have an oxygen atom at a terminal bonding site include an alkylgroup having 1 to 15 carbon atoms, an alkenyl group having 2 to 15carbon atoms, an alkoxy group having 1 to 15 carbon atoms, an aryl grouphaving 6 to 10 carbon atoms, an aryloxy group having 6 to 10 carbonatoms, a heteroaryl group and a heteroaryloxy group. These groups are asdefined above, and specific examples thereof are also as describedabove.

R¹ and R² may bond to each other, or R² and R³ may bond to each other,and form a ring that may have a hetero atom, a double bond or asubstituent. The above hetero atom is at least one atom selected fromoxygen atoms, nitrogen atoms and sulfur atoms. The ring that is formedincludes lactam, pyrrolidine, piperidine, morpholine and hydantoin. Whenthe ring that is formed has a substituent, the substituent includesthose represented by each of the above X¹ to X⁵.

When two members of X¹, X² and X³ bond to adjacent two carbon atoms, thetwo members may bond to each other and form a benzene ring or amethylenedioxy group.

The compound of the above general formula (I) preferably includes acompound of the general formula (I) wherein at least one of X⁴ and X⁵ isa group represented by any one of the following general formula (II) to(V),

—OCH₂—R¹¹  (III)—CH═CH—R¹¹  (IV)—C≡C—R¹¹  (V)

in which R⁴ is a hydrogen atom or an alkyl group having 1 to 15 carbonatoms and R¹¹ is a group of the general formula (VI) or (VII).

In the above general formulae (VI) and (VII), each of R⁵ and R⁶ isindependently a hydrogen atom, a substituent having no organic group, ahydrocarbon or heteroaryl group that bonds to a benzene ring or anaromatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group, —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷)SO₂R⁸,—N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸. In the above formulae, further, Het is anaromatic heterocyclic ring and R¹⁰ is a hydrogen atom or an alkyl grouphaving 1 to 15 carbon atoms.

Examples of the substituent having no organic group, represented by eachof the above R⁵ and R⁶, include a halogen atom, a nitro group, a cyanogroup, a hydroxyl group and a carboxyl group. Examples of thehydrocarbon or heteroaryl group that bonds to the benzene ring or thearomatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group include an alkyl group having 1 to 15carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynylgroup having 2 to 15 carbon atoms, an aryl group having 6 to 10 carbonatoms, a heteroaryl group, an alkoxy group having 1 to 15 carbon atoms,an aryloxy group having 6 to 10 carbon atoms, a heteroaryloxy group, analkoxycarbonyl group having 2 to 16 carbon atoms, an aryloxycarbonylgroup having 7 to 11 carbon atoms, a heteroaryloxycarbonyl group, analkylcarbonyl group having 2 to 16 carbon atoms, an arylcarbonyl grouphaving 7 to 11 carbon atoms, a heteroarylcarbonyl group, analkylcarbonyloxy group having 2 to 16 carbon atoms, an arylcarbonyloxygroup having 7 to 11 carbon atoms, a heteroarylcarbonyloxy group, analkylthio group having 1 to 15 carbon atoms, an arylthio group having 6to 10 carbon atoms, a heteroarylthio group, an alkylsulfonyl grouphaving 1 to 15 carbon atoms, an arylsulfonyl group having 6 to 10 carbonatoms, a heteroarylsulfonyl group, an alkylsulfinyl group having 1 to 15carbon atoms, an arylsulfinyl group having 6 to 10 carbon atoms and aheteroarylsulfinyl group.

The alkyl group represented by each of R⁴, R⁵, R⁶ and R¹⁰ is as definedwith regard to the already explained alkyl group, and specific examplesthereof are also as described with regard to the already explained alkylgroup. The halogen atom, aryl group, alkoxy group, aryloxy group,heteroaryloxy group, alkoxycarbonyl group, alkylcarbonyl group,arylcarbonyl group, heteroarylcarbonyl group, alkylcarbonyloxy group,arylcarbonyloxy group, heteroarylcarbonyloxy group, alkylthio group,arylthio group, heteroarylthio group, alkylsulfonyl group, arylsulfonylgroup, heteroarylsulfonyl group, alkylsulfinyl group, arylsulfinyl groupand heteroarylsulfinyl group represented by each of R⁵ and R⁶ are asdefined with regard to the already explained corresponding groups, andspecific examples thereof are also as described with regard to thealready explained corresponding groups.

In the above —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷)SO₂R⁸, —N(R⁷)CONR⁸R⁹ and—CONR⁷R⁸, each of R⁷, R⁸ and R⁹ is independently a hydrogen atom or ahydrocarbon or heteroaryl group that may have an oxygen atom at aterminal bonding site. Examples of the hydrocarbon or heteroaryl groupthat may have an oxygen atom at a terminal bonding site include an alkylgroup having 1 to 15 carbon atoms, an alkenyl group having 2 to 15carbon atoms, an alkoxy group having 1 to 15 carbon atoms, an aryl grouphaving 6 to 10 carbon atoms, an aryloxy group having 6 to 10 carbonatoms, a heteroaryl group and a heteroaryloxy group. These groups are asdefined with regard to the already explained corresponding groups, andspecific examples thereof are also as described with regard to thealready explained corresponding groups.

Further, R⁷ and R⁸ may bond, or R⁸ and R⁹ may bond, to each other andform a ring that may contain a hetero atom, a double bond or asubstituent. The above ring is also as explained with regard to theabove R¹ and R² or the above R² and R³.

Further, the compound of the above general formula (I) is preferably acompound of the general formula (I) wherein at least one of X¹, X² andX³ is —NR¹R², —N(R¹)COR², —N(R¹)SO₂R₂, —N(R¹)CONR²R³, an alkyl group, analkoxy group, an aryl group, a heteroaryl group, an alkoxycarbonylgroup, a halogen atom, a cyano group or an alkylthio, and particularlypreferably a compound of the general formula (I) wherein at least one ofX¹, X² and X³ is —N(R¹)COR² substituted on the 3-position.

When the compound of the above general formula (I), provided by thepresent invention, has an asymmetric carbon, the compound of the presentinvention includes a racemate thereof, a diastereo isomer thereof andindividual optically active compounds thereof. When geometrical isomersexist, the present invention also includes (E)- and (Z)-configurationcompounds and a mixture of these.

The salt of the compound of the above general formula (I), provided bythe present invention, is not specially limited so long as it is apharmaceutically acceptable salt. Examples of the salt include a saltwith an inorganic base, a salt with an organic base, a salt with anorganic acid, a salt with an inorganic acid and a salt with an aminoacid. Examples of the salt with an inorganic base include alkali metalsalts such as a sodium salt, a potassium salt and a calcium salt and anammonium salt. Examples of the salt with an organic base include atriethylamine salt, a pyridine salt, an ethanolamine salt, acyclohexylamine salt and a dicyclohexylamine salt. Examples of the saltwith an organic acid include a formate, an acetate, a tartarate, amaleate, a succinate and a methanesulfonate. Examples of the salt withan inorganic acid include a hydrochloride, a hydrobromate and a nitrate.Examples of the salt with an amino acid include a glycine salt, analanine salt, an arginine salt, a glutamate and an aspartate.

The compound of the general formula (I), provided by the presentinvention, can be produced by the following preparation method A.

wherein X¹ to X⁵ and Het are as defined in the above general formula(I), R^(a) is an alkyl group having 1 to 15 carbon atoms, and Hal is ahalogen atom.(Step 1)

A phenyl acetate derivative of the general formula 1 is reacted with abase such as lithium diisopropylamide in a proper neutral solvent (suchas tetrahydrofuran) at a low temperature to generate an enolate anion,and then the enolate anion is reacted with a halide of the generalformula 2, whereby a corresponding compound of the general formula 3 canbe prepared.

(Step 2)

The alkyl ester derivative of the general formula 3 is decomposed withan aqueous solution of an alkali such as lithium hydroxide, sodiumhydroxide or potassium hydroxide under an alkaline condition, whereby acompound of the general formula 4 can be prepared. While any reactionsolvent can be used without any limitation so long as it is misciblewith water, the solvent is preferably selected from methanol, ethanol,tetrahydrofuran, 1,4-dioxane or dimethoxyethane. The reactiontemperature is not critical, and the reaction is generally carried outat 0 to 100° C. The reaction time period is preferably 30 minutes to 6hours.

The compound of the general formula (2) for use in the above step 1,when it is a picolyl halide, can be synthesized according to thefollowing preparation method B.

wherein each of X⁴, X⁵ and Hal are as defined above, and R^(b) is analkyl group having 1 to 15 carbon atoms.(Step 1)

An ethyl nicotinate derivative of the general formula 5 is reacted witha reducing agent such as lithium aluminum hydride in a proper neutralsolvent (such as tetrahydrofuran), whereby a corresponding compound ofthe general formula 6 can be prepared.

(Step 2)

A hydroxyl group on the compound of the general formula 6 can bereplaced with a chlorine atom, a bromine atom or an iodine atomaccording to a method well known and recognized in the field of thisart. For example, the compound of the general formula 6 is reacted withtriphenylphosphine and carbon tetrabromide in dichloromethane, wherebythe above hydroxyl group can be replaced with a bromide. While anyreaction solvent can be used without any limitation so long as it doesnot greatly impair the reaction, the solvent is preferably selected fromdichloromethane, chloroform or 1,2-dichloroethane.

The compound of the present invention, prepared by the above method, isisolated and purified in the form of a free compound, a salt thereof,any one of various solvents thereof (e.g., hydrate, ethanol solvate orthe like) or a crystal polymorph substance. When the compound of thepresent invention is a salt, a pharmaceutically acceptable salt can beprepared according to a conventional salt-forming reaction. Theisolation and purification are carried out by chemical procedures suchas extraction, crystallization, fractionation chromatography of varioustypes, or the like. An optical isomer can be obtained by asymmetricsynthesis or by selecting proper starting compounds, or the compound ofthe present invention can be obtained as a stereo-chemically pure isomerby optical resolution of a racemic compound.

Tables 1 to 4 show examples of the substituents on the compound of thegeneral formula (I), provided by the present invention. After Table 4,there are illustrated structural formulae of examples of compounds oftypes different from the type of the compounds shown in Tables 1 to 4.

TABLE 1

Compound No. X¹ X² X³ X⁴ X⁵ 1

MeO—(4-) H

H 2

MeO—(4-) H

H 3

MeO—(4-) H

H 4

MeO—(4-) H

H 5

MeO—(4-) H

H 6

EtO—(4-) H

H 7

EtO—(4-) H

H

TABLE 2

Compound No. X¹ X² X³ X⁴ X⁵ 8

EtO—(4-) H

H 9

EtO—(4-) H

H 10

EtO—(4-) H

H 11

H H

H 12

H H

H 13

H

H 14

H

H

TABLE 3

Compound No. X¹ X² X³ X⁴ X⁵ 15

H

H 16

H

H 17

Et—(4-) H

H 18

Et—(4-) H

H 19

F₃C—(5-) H

H 20

MeO—(4-) H

H 21

MeO—(4-) H

H

TABLE 4

Compound No. X¹ X² X³ X⁴ X⁵ 22

MeO—(4-) H

H 23

MeO—(4-) H

H 24 MeO—(2-) MeO—(5-) H

H 25

H

H 26

H

H

In Tables, Me represents methyl and Et represents ethyl.

The 2-phenyl-3-heteroarylpropionic acid derivative and its salt,provided by the present invention, exhibit excellent VLA-4 and/or LPAM-1antagonistic action and are useful as a therapeutic or prophlacticpharmaceutical agent against diseases caused by adhesion andinfiltration of leucocyte or diseases in which VLA-4 and/orLPAM-1-dependent adhesion process plays some role. The above diseasesinclude autoimmune diseases such as rheumaticoid arthritis, systemiclupus erythematosus, multiple sclerosis and Sjögren's syndrome, variousorgan inflammations caused together with theses, allergic diseases suchas asthma, atopic dermatitis, congested nose and rhinitis, inflammatorybowel diseases including Crohn's disease, nephritis, hepatitis,inflammatory diseases of central nerve system, cardiovascular disease,arteriosclerosis, diabetes and various malignant tumors. It is also usedpreventing damage of transplant organ, and blocking of proliferation andmetastasis of tumor.

The compound of the present invention is systemically or topicallyadministered by any one of methods such as an oral method, anintravenous injection method, a hypodermic injection method, anintra-rectum administration method and the like. Of these, oraladministration is desirable. Further, the dosage form can be selected asrequired depending upon an administration route and includes, forexample, a tablet, a troche, a sublingual tablet, a sugar-coated tablet,a capsule, a ball, powdered medicine, granules, liquid medicine, anemulsifiable concentrate, a syrup, a respiratory tonic, an ophthalmicsolution, a collunarium, an injectable solution and a suppository.Further, these preparations can be produced by incorporating a dilutingagent, an antiseptic agent, a wetting agent, an emulsifier, a stabilizerand a solubilizing agent.

The dose of the compound of the present invention can be determined asrequired depending upon conditions such as an administration route, apatient to whom it is to be administered, a symptom and the like. Forexample, when it is administered to an adult patient, the dose, or anamount at one time, of the compound of the present invention as anactive ingredient is in the range of approximately 0.1 to 100 mg/kg,preferably 1 to 30 mg/kg, and preferably, it is administered once tothree times a day.

EXAMPLES

The present invention will be explained with reference to Exampleshereinafter, while the present invention shall not be limited by theseExamples.

In ¹H-NMR spectrum measured in Examples below, tetramethylsilane (TMS)was used as an internal standard, the measurement was made with aJNM-EX270 model spectrometer (270 MHz, manufactured by JEOL Ltd.), and δvalues were shown by ppm. Coupling constants (J) were shown by Hz, andin the resolution mode, the following abbreviations were used.s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Formeasurement of low-resolution mass spectrum (FABMS), a JMS-HX-110A modelmanufactured by JEOL Ltd. was used.

In the following general formulae and Tables, Me represents methyl, andEt represents ethyl.

Example 1 Preparation of3-[2-(2,6-dichlorobenzoylamino)pyrid-5-yl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionicacid

A compound (I-a) having the following structure was prepared accordingto the following reaction scheme.

wherein NMM is N-methylmorpholine and LDA is lithiumdiisopropylamide.

11.5 Grams (83 mmol) of 6-aminonicotinic acid (a) was dissolved in 85 mlof ethanol, 2.5 ml of concentrated sulfuric acid was added, and themixture was refluxed under heat for 24 hours. The solvent was removedunder vacuum, 150 ml of ice water was poured, and a saturated sodiumhydrogen carbonate aqueous solution was added. The mixture was subjectedto extraction with ethyl acetate, the extract was dried over anhydrousmagnesium sulfate, and the solvent was evaporated off under vacuum togive 10.0 g (yield 73%) of ethyl 6-aminonicotinate ester (b) in the formof a white solid.

10.0 Grams (60 mmol) of ethyl 6-aminonicotinate ester (b) was dissolvedin 150 ml of dichloromethane, and 9.2 ml (84 mmol) of N-methylmorpholinewas added. At 0° C., 9.5 ml (66 mmol) of 2,6-dichlorobenzoyl chloride(c) was added, and the mixture was stirred at room temperature for 24hours.

Further, 9.2 ml (84 mmol) of N-methylmorpholine and 9.5 ml (66 mmol) of2,6-dichlorobenzoyl chloride (c) were added, and the mixture was stirredfor 4 days. Water was added, and the solvent was removed under vacuum.

Water was added, the mixture was subjected to extraction with ethylacetate, and the extract was dried over anhydrous magnesium sulfate. Thesolvent was evaporated off under vacuum, and the residue was purified bysilica gel column chromatography (chloroform:methanol (volumeratio)=400:1-200:1), to give 14.0 g (yield 45%) of ethylN,N-bis(2,6-dichlorobenzoyl)-6-aminonicotinate ester (d).

14.0 Grams (27 mmol) of ethylN,N-bis(2,6-dichlorobenzoyl)-6-aminonicotinate ester (d) was dissolvedin 200 ml of tetrahydrofuran. At 0° C., a solution of 21 g (55 mmol) oflithium aluminum hydride in 200 ml of tetrahydrofuran was dropwiseadded, and the mixture was stirred for 2.5 hours. The reaction wasstopped with 15 ml of ethyl acetate and an ammonium chloride aqueoussolution, the reaction mixture was extracted with ethyl acetate, and theextract was washed with a sodium chloride aqueous solution. The extractwas dried over anhydrous magnesium sulfate, the solvent was evaporatedoff under vacuum, and the residue was purified by silica gel columnchromatography (chloroform:methanol (volume ratio)=25:1), to give 3.4 g(yield 27%) of2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide(e).

In 40 ml of dichloromethane was dissolved 855 mg (1.8 mmol) of2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide(e), and 905 mg (2.7 mmol) of carbon tetrabromide and 573 mg (2.2 mmol)of triphenylphosphine were added. The mixture was stirred for 2.5 hours,and treated with a saturated sodium hydrogen carbonate aqueous solution.The mixture was subjected to extraction with chloroform, and the extractwas washed with a saturated sodium chloride aqueous solution. Thesolvent was evaporated off under vacuum, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate (volumeratio)=3:1-2:1) to give 631 mg (yield 65%) of2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide(f).

In 600 ml of ethanol was dissolved 25.0 g (127 mmol) of4-hydroxy-3-nitrophenylacetic acid, 3.2 ml of concentrated sulfuric acidwas added, and the mixture was refluxed under heat for 6 hours. Afterthe reaction, the solvent was removed under vacuum, and the residue wasdissolved in ethyl acetate. The mixture was washed with water, a sodiumhydrogen carbonate aqueous solution and a sodium chloride aqueoussolution, and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, to give 28.3 g (yield 99%) ofethyl 4-hydroxy-3-nitrophenylacetate ester in the form of a yellowsolid.

28.2 Grams (125 mmol) of ethyl 4-hydroxy-3-nitrophenylacetate ester wasdissolved in 700 ml of acetone, 23.4 ml (376 mmol) of methyl iodide wasadded in the presence of 86.5 g (626 mmol) of potassium carbonate, andthe mixture was refluxed under heat for 3 hours. A solid was filteredoff, then the solvent was removed under vacuum, and the residue wasdissolved in ethyl acetate. The solution was washed with a sodiumchloride aqueous solution and then dried over anhydrous sodium sulfate.The solvent was removed under vacuum, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate (volumeratio)=3:1), to give 29.6 g (yield 99%) of ethyl4-methoxy-3-nitrophenylacetate ester.

13.5 Grams (56 mmol) of ethyl 4-methoxy-3-nitrophenylacetate ester, 6.1ml (67 mmol) of isobutyl aldehyde and 1.3 g of 10 wt % palladium carbonwere dissolved in 280 ml of methanol, and the mixture was stirred undera hydrogen atmosphere (0.29 MPa) for 14 hours. The palladium carbon wasfiltered off with cerite, then, the solvent was removed under vacuum,and the residue was purified by silica gel column chromatography(hexane: ethyl acetate (volume ratio)=6:1) to give 14.8 g (yield 100%)of ethyl 3-isobutylamino-4-methoxyphenyl acetate ester in the form of ayellow syrup.

31.2 Grams (117 mmol) of ethyl 3-isobutylamino-4-methoxyphenyl acetateester was dissolved in 600 ml of dichloromethane, and 15.9 ml (129 mmol)of pivaloyl chloride was added at 0° C. Further, 36.1 ml (259 mmol) oftriethylamine was added, and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was treated with a sodium hydrogencarbonate aqueous solution and subjected to extraction with chloroform.The extract was washed with a sodium chloride aqueous solution and thendried over anhydrous sodium sulfate. The solvent was removed undervacuum, and the residue was purified by silica gel column chromatography(hexane:ethyl acetate (volume ratio)=3:1) to give 36.2 g (yield 89%) ofethyl 3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenylacetateester (g) in the form of a white solid.

Dissolved in 5 ml of tetrahydrofuran was 150 mg (0.43 mmol) of ethyl3-[(2,2-dimethylpropionyl)-isobutylamino]-4-methoxyphenylacetate ester(g), and 0.26 ml (0.52 mmol) of a solution of 2 mol/l oflithiumdiisopropylamide in heptane, tetrahydrofuran and ethylbenzene wasdropwise added at −78° C. The mixture was stirred for 30 minutes, andthen a solution of 277 mg (0.52 mmol) of2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide (f) in 5 ml of tetrahydrofuran was dropwiseadded. The mixture was temperature-increased to room temperature,stirred further for 1 hour, and treated with 1 mol/liter of hydrochloricacid. The reaction mixture was subjected to extraction with ethylacetate, and the extract was dried over anhydrous magnesium sulfate. Thesolvent was evaporated off under vacuum, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate (volumeratio)=2:1), to give 245 mg (yield 71%) of ethyl3-{6-[bis(2,6-dichlorobenzoyl)amino]pyrid-3-yl}-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionateester (h)

Dissolved in a solvent mixture of 5 ml of methanol with 5 ml oftetrahydrofuran was 240 mg (0.3 mmol) of ethyl3-{6-[bis(2,6-dichlorobenzoyl)amino]pyrid-3-yl}-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionateester (h), 49 mg (0.91 mmol) of sodium methoxide was added, and themixture was refluxed under heat for 17 hours. The solvent was removedunder vacuum, and then the reaction mixture was treated with 1 mol/literof hydrochloric acid. The reaction mixture was subjected to extractionwith ethyl acetate and washed with a saturated sodium chloride aqueoussolution. The reaction mixture was dried over anhydrous magnesiumsulfate, and the solvent was removed under vacuum. The residue wasdissolved in a solvent mixture of 5 ml of methanol with 5 ml oftetrahydrofuran, 0.45 ml (0.9 mmol) of a sodium hydroxide (2 mol/liter)aqueous solution was added, and the mixture was stirred for 16 hours.The reaction mixture was treated with 1 mol/liter of hydrochloric acid.The solvent was evaporated off under vacuum, waster was added to theresidue, and a precipitate was recovered by filtration. The precipitatewas purified by silica gel column chromatography (chloroform:methanol(volume ratio)=20:1-10:1), to give 50 mg (yield 28%) of3-[6-(2,6-dichlorobenzoylamino)pyrid-3-yl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionicacid (I-a).

The following Table 5 shows physical property values thereof.

Compounds of Examples 2 to 10 shown in the following Tables 5, 6 and 7were prepared in the same manner as in Example 1. The following Tables5, 6 and 7 shows physical property values thereof.

TABLE 5

Example R² X² NMR, MS 1

—OMe ¹H-NMR(DMSO-d₆)δ: 0.78-0.95(15H, m), 1.50-1.75(1H, m),2.57-2.67(1H,m), 3.00-3.20(1H, m), 3.25-3.30(1H, m),3.84(3H, s), 3.92-4.05(2H, m),7.00-7.20(2H, m),7.35-7.48(1H, m), 7.53-7.61(3H, m), 7.70-7.80(1H, m),8.05-8.20(2H, m), 11.23(1H, brs). FABMS: 600(M+H)⁺. 2

—OMe ¹H-NMR(DMSO-d₆)δ: 0.73-0.91(12H, m), 1.44-1.58(1H,m), 1.97-2.22(1H,m), 2.84-3.05(2H, m), 3.21-3.29(1H,m), 3.58-3.69(1H, m), 3.77(3H, s),3.91(1H, m),7.03-7.11(2H, m), 7.32(1H, t, J=10.4Hz), 7.42-7.54(3H, m),7.61(1H, t, J=8.7Hz), 8.01-8.07(2H, m), 11.15&11.16(1H, s), 12.48(1H,brs). FABMS: 586 (M+H)⁺. 3

—OMe ¹H-NMR(DMSO-d₆)δ: 0.56-0.65(3H, m), 0.72-0.86(9H,m), 1.06-1.56(6H,m), 1.68-1.91(1H, m), 2.81-3.05(2H,m), 3.22(1H, m), 3.75(3H, s),3.82-3.92(1H, m), 7.00(1H,d, J=18.5Hz), 7.09(1H, d, J=8.9Hz), 7.33(1H,t, J=6.8Hz), 7.42-7.66(4H, m), 8.00-8.08(2H, m), 11.17&11.18(1H, s),12.47(1H, brs). FABMS: 614 (M+H)⁺. 4

—OMe ¹H-NMR(DMSO-d₆)δ: 0.79(3H, d, J=5.3Hz), 0.85(3H,s), 1.47-1.58(1H,m), 2.89-3.05(2H, m), 3.20-3.26(1H,m), 3.42-3.47(1H, m), 3.71(3H, s),3.81-3.85(1H, ,m),4.91-5.11(2H, m), 6.99-7.04(2H, m), 7.11-7.30(5H,m),7.39(1H, m), 7.42-7.56(3H, m), 7.64(1H, d, J=6.9Hz), 8.02-8.13(2H,m), 11.16(1H, s), 12.27-12.58(1H, m). FABMS: 650(M+H)⁺.

TABLE 6

Example R² X² NMR, MS 5

—OEt ¹H-NMR(DMSO-d₆)δ: 0.71-0.89(12H, m), 1.26(3H, t, J=6.8Hz),1.40-1.65(1H, m), 1.98-2.25(1H, m),3.02-3.05(2H, m), 3.06-3.32(1H, m),3.47-3.60(1H, m),3.92(1H, m), 4.03(2H, q, J=6.9Hz), 7.06(2H, d, J=8.9Hz), 7.28(1H, brs), 7.46-7.62(4H, m), 8.00-8.05(2H, m), 11.15(1H, s).FABMS: 600(M+H)⁺. 6

—OEt ¹H-NMR(DMSO-d₆)δ: 0.72-0.89(15H, m), 1.27(3H, t, J=6.3Hz),1.40-1.70(1H, m), 2.63-2.68(1H, m), 3.00(1H, m),3.23(1H, m),3.78-4.06(4H, m), 7.01(2H, d, J=8.3Hz),7.31(1H, m), 7.42-7.53(3H, m),7.64(1H, m), 7.99-8.10(2H, m), 11.15(1H, s), 12.46(1H, brs). FABMS:614(M+H)⁺. 7

—OEt ¹H-NMR(DMSO-d₆)δ: 0.55-0.67(6H, m), 0.71-0.85(6H,m), 1.17-1.19(2H,m), 1.27(3H, t, J=6.8Hz),1.35-1.43(2H, m), 1.70-1.91(1H, m),2.95-3.05(2H, m),3.21(1H, m), 3.66-3.69(1H, m), 3.88-4.05(4H,m),7.00(1H, d, J=15.8Hz), 7.06(1H, d, J=8.6Hz), 7.29(1H, m),7.42-7.65(4H, m), 7.94-8.11(2H, m), 11.16(1H, s), 12.45(1H, brs).FABMS:628 (M+H)⁺. 8

—OEt ¹H-NMR(DMSO-d₆)δ: 0.80(3H, s), 0.84(3H, s), 1.21(3H,s),1.40-1.65(1H, m), 2.80-3.05(1H, m), 3.06-3.20(2H,m), 3.35-3.50(1H, m),3.80-4.00(3H, m), 4.90-5.15(2H,m), 6.99-7.05(2H, m), 7.19-7.63(10H, m),8.02-8.14(2H,m), 11.17(1H, s). FABMS: 664(M+H)⁺.

TABLE 7

Example R² X² NMR, MS 9

—OMe ¹H-NMR(DMSO-d₆)δ: 0.70-0.88(15H, m), 1.50-1.75(1H, m),2.48-2.52(1H,m), 2.92-3.07(1H, m), 3.22-3.28(1H, m),3.77(3H, s), 3.91-3.95(2H, m),6.98-7.08(2H, m),7.30-7.38(1H, m), 7.63-7.70(1H, m), 7.95-8.21(2H, m),8.74(2H, s), 11.35(1H, brs), 12.44(1H, brs). FABMS: 601(M+H)⁺. 10

—OEt ¹H-NMR(DMSO-d₆)δ: 0.71-0.89(15H, m), 1.27(3H, t,J=6.6Hz),1.35-1.60(1H, m), 2.56-2.76(1H, m),2.98-3.06(1H, m), 3.21-3.23(1H, m),3.77-4.06(4H, m),7.00-7.07(2H, m), 7.27-7.34(1H, m), 7.65-7.68(1H, m),7.97-8.12(2H, m), 8.74(2H, s), 11.35&11.38(1H, s), 12.47(1H, brs).FABMS: 615(M+H)⁺.

Test Example 1 VLA-4/VCAM-1 Adhesion Inhibition Test

The compound of the present invention was evaluated for inhibitionactivity against the adhesion between Chinese hamster ovary cells (CHOcell) transfected with a human VCAM-1 gene and promyelocyte-like cellline HL-60 that exhibiting VLA-4 according to the following method.

The above VCAM-1 expressing CHO cells were placed in a 96-well cultureplate in amount of 7×10³ cells per well and cultured in Ham's F-12medium containing 10 wt % fetal calf serum (FCS) for 3 days until aconfluent state was satisfied. The HL-60 cells were re-floated in Hanks'solution containing 0.4 wt % bovine serum albumin (BSA), and 5 μM of2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein penta acetoxy methylester (BCECF-AM) was added to label the cells. Solutions having variousconcentrations of each test substance and having an amount of 20 μl eachwere added to 180 μl each of suspensions of BCECF-labeled HL-60 cellsre-floated at a rate of 4×10⁶ cells/ml in the FCS-non-containing RPMI1640 culture medium, and pre-treated at 37° C. for 15 minutes.

Then, the pre-treated HL-60 cells were stratified in the 96-well plateculturing the VCAM-1 expressing CHO cells at a rate of 2×10⁵ cells perwell, and allowed to adhere thereto at 37° C. for 5 minutes. Then, theplate was filled with 0.4 wt % BSA Hanks, covered with a plate sealerand turned upside down. Further, the cells were cultured for 45 minutes.After washing, 1 wt % NP-40-containing PBS was added to destroy thecells, and the thus-obtained supernatants were measured for fluorescenceintensity with a cyto Fluor 2300 fluorescence measurement system(supplied by Millipore).

Further, as a blank, 1 wt % NP-40-containing PBS was measured forfluorescence intensity. Further, as standards, a fluorescence-labeledHL-60 floating liquid was added to 1 wt % NP-40-containing PBS at a rateof 2×10⁵, 10⁵, 2×10⁴ and 10⁴ cells/ml, the cells were destroyed, and thethus-obtained supernatants were measured for fluorescence intensity.

Each test substance was measured as described above, and on the basis ofthe calibration curve prepared from the measurements of the standard,cells in a control and cells adhering to the VCAM-1 expressive CHO cellsdue to the addition of the test substances were measured for numbers,and cell adhesion inhibition ratios (%) were calculated on the basis ofthe following equation.

Cell adhesion inhibition ratio (%)=100×[1−(number of adhered cells ofgroups to which the test substance was added/number of adhered cells ofcontrol groups)

The following Table 8 shows 50% inhibition concentrations of the testsubstances calculated in this Test Example.

TABLE 8 Example 50% inhibition concentration (nM) 1 3 2 12 3 33 5 48 613 7 7.3 9 2.8 10 1.2

When the LPAM-1/VCAM-1 adhesion inhibition test was conducted withregard to Examples 1, 9 and 10, adhesion inhibition activity was found.

INDUSTRIAL UTILITY

According to the present invention, there can be provided a novel2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof, whichis effective for the therapy and prophylactic of diseases caused throughVLA-4 and/or LPAM-1, which is excellent in oral absorption and in-vivomoving state and which exhibits VLA-4 and/or LPAM-1 antagonisticactivity. According to the present invention, further, there can beprovided a VLA-4 and/or LPAM-1 antagonist and pharmaceutical agent,which are useful as a pharmaceutical agent for the therapy or preventionof diseases caused through VLA-4 and/or LPAM-1 such as diseases causedby adhesion and infiltration of leucocyte or diseases in which a VLA-4and/or LPAM-1 dependent adhesion process plays a certain role.

1. A 2-phenyl-3-heteroarylpropionic acid derivative of the generalformula (I),

wherein Het is an aromatic heterocyclic ring selected from the groupconsisting of pyridinone, indole, pyrrole, thiazole, furan, thiophene,oxazole, pyridine, pyrimidine, pyrazine, quinoline, and phthalimide, andeach X1, X2 or X3 is independently a hydrogen atom, a hydrocarbon groupthat bonds to the benzene ring directly or via oxygen, —N(R¹)COR², inwhich each of R¹ and R² is independently a hydrogen atom or ahydrocarbon or heteroaryl group which may have an oxygen atom at aterminal bonding site, and R¹ and R² may bond to each other and form aring that may contain a hetero atom, a double bond or a substituent,provided that when two substituents of X1, X2 and X3 bond to adjacentcarbon atoms, the two substituents may bond to each other and form abenzene ring or a methylenedioxy group, and wherein at least one of X4and X5 in the general formula (I) is a group represented by any one ofthe general formulae (II) to (V):

—OCH₂—R¹¹  (III)—CH═CH—R¹¹  (IV)—C≡C—R¹¹  (V) wherein R⁴ is a hydrogen atom or an alkyl group having 1to 15 carbon atoms and R¹¹ is a group represented by the general formula(VI) or (VII),

wherein each of R⁵ and R⁶ is independently a hydrogen atom, a halogenatom, a nitro group, a cyano group, a hydroxyl group, a carboxyl groupor a hydrocarbon or heteroaryl group that bonds to the benzene ring orthe aromatic heterocyclic ring directly or through an oxygen atom, asulfur atom, an oxycarbonyl group, a carbonyl group, a carbonyloxygroup, a sulfonyl group or a sulfinyl group, —NR7R8, —N(R⁷)COR⁸,—N(R⁷)SO2R⁸, —N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸, in which each of R⁷, R⁸ and R⁹is independently a hydrogen atom or a hydrocarbon or heteroaryl groupwhich may have an oxygen atom at a terminal bonding site, and R⁷ and R⁸may bond, or R⁸ and R⁹ may bond, to each other and form a ring that maycontain a hetero atom, a double bond or a substituent, Het is anaromatic heterocyclic ring and R¹⁰ is a hydrogen atom or an alkyl grouphaving 1 to 15 carbon atoms, or a salt thereof.
 2. The2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in claim 1, wherein at least one of X¹, X² and X³ in the generalformula (I) is —N(R¹)COR², an alkyl group, or an alkoxy group.
 3. The2-phenyl-3-heteroarylpropionic acid derivative or salt thereof asrecited in claim 2, wherein at least one of X¹, X² and X³ is —N(R¹)COR²substituted on the 3-position.